Synthesis and Structural Characterization of Novel Trihalo-sulfone Inhibitors of WNK1.

ABSTRACT: With No lysine (K) [WNK] kinases are structurally unique serine/threonine protein kinases that have therapeutic potential for blood pressure regulation and cancer. A novel class of trihalo-sulfone compounds was identified by high-throughput screening. Trihalo-sulfone 1 emerged as an effective inhibitor of WNK1 with an IC₅₀ value of 1.6 μM. Herein, we define chemical features necessary for inhibition of WNK1 using chemical synthesis and X-ray crystallography. Analogues that probed the role of specific functional groups to the inhibitory activity were synthesized. X-ray structures of trihalo-sulfone 1 and a second trihalo-sulfone 23 bound to WNK1 revealed active site binding to two of the three previously defined canonical inhibitor binding pockets as well as

SUBMITTER: Rodriguez M 

PROVIDER: S-EPMC9575160 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature